Esquire started in 1933 as a quarterly press run of a hundred thousand copies. It cost fifty cents per copy (equivalent to $9.25 today).[7] It later transformed itself into a more refined periodical with an emphasis on men's fashion and contributions by Ernest Hemingway, F. Scott Fitzgerald,[8]Alberto Moravia, André Gide, and Julian Huxley. In the 1940s, the popularity of the Petty Girls and Vargas Girls provided a circulation boost. In the 1960s, Esquire helped pioneer the trend of New Journalism by publishing such writers as Norman Mailer, Tim O'Brien, John Sack, Gay Talese, Tom Wolfe, and Terry Southern. In August 1969, Esquire published Normand Poirier's piece, "An American Atrocity", one of the first reports of American atrocities committed against Vietnamese civilians.[9] Under Harold Hayes, who ran it from 1961 to 1973, it became as distinctive as its oversized pages.[10] The magazine shrank to the conventional 8½×11 inches in 1971. The magazine was sold by the original owners to Clay Felker in 1977, who reinvented the magazine as a fortnightly in 1978, under the title of Esquire Fortnightly. However, the fortnightly experiment proved to be a failure, and by the end of that year, the magazine lost US$5 million. Felker sold Esquire in 1979 to the 13-30 Corporation, a Tennessee publisher, whose owners refocused the magazine into a monthly. During this time, New York Woman magazine was launched as something of a spinoff version of Esquire aimed at female audience. 13-30 split up in 1986, and Esquire was sold to Hearst at the end of the year, with New York Woman going its separate way to American Express Publishing.

In January 2009 Esquire launched a new blog—the Daily Endorsement Blog. Each morning the editors of the magazine recommend one thing for readers' immediate enjoyment: "not a political candidate or position or party, but a breakthrough idea or product or Web site."[12] The concept for this blog probably emerged from the November 2008 "Endorsement Issue", in which, after 75 years, Esquire publicly endorsed a presidential candidate for the first time.[13] The Daily Endorsement Blog was officially discontinued on April 2011.

From 1969 to 1976, Gordon Lish served as fiction editor for Esquire and became known as "Captain Fiction" because of the authors whose careers he assisted. Lish helped establish the career of writer Raymond Carver by publishing his short stories in Esquire, often over the objections of Hayes.[14] Lish is noted for encouraging Carver's minimalism and publishing the short stories of Richard Ford. Using the influential publication as a vehicle to introduce new fiction by emerging authors, he promoted the work of such writers as T. Coraghessan Boyle, Barry Hannah, Cynthia Ozick and Reynolds Price.

In February 1977, Esquire published "For Rupert – with no promises" as an unsigned work of fiction: this was the first time it had published a work without identifying the author. Readers speculated that it was the work of J. D. Salinger, the reclusive author best known for The Catcher in the Rye. Told in first-person, the story features events and Glass family names from the story "For Esmé – with Love and Squalor". Gordon Lish is quoted as saying, "I tried to borrow Salinger's voice and the psychological circumstances of his life, as I imagine them to be now. And I tried to use those things to elaborate on certain circumstances and events in his fiction to deepen them and add complexity."[15]

In 2007 Esquire launched the Napkin Fiction Project, in which 250 cocktail napkins were mailed to writers all over the country by the incoming fiction editor, in a playful attempt to revive short fiction—"some with a half dozen books to their name, others just finishing their first."[17] In return, the magazine received nearly a hundred stories. Rick Moody, Jonathan Ames, Bret Anthony Johnston, Joshua Ferris, Yiyun Li, Aimee Bender, and ZZ Packer are among the notable writers included.

For many years, Esquire has published its annual Dubious Achievement Awards, lampooning events of the preceding year. As a running gag, the annual article almost always displayed an old photo of Richard Nixon laughing, with the caption, "Why is this man laughing?" However, the February 2006 "Dubious Achievement Awards" used the caption under a photo of W. Mark Felt, the former FBI official revealed in 2005 to be the "Deep Throat" Watergate source for Bob Woodward and Carl Bernstein. The magazine did continue the Nixon photo in February 2007, referring to a poll stating that George W. Bush had surpassed Nixon as the "worst president ever". Another running gag has been headlining one especially egregious achievement, "And then they went to Elaine's." (Elaine's was a popular restaurant in New York City. It closed May 2011.)

Esquire did not publish "Dubious Achievement Awards" for 2001, but resumed them with the 2002 awards, published in the February 2003 issue.

"Dubious Achievement Awards" were discontinued in 2008, according to an editor's note in the January 2008 issue.[18] However, after a nine-year hiatus, the feature was revived in the January 2017 issue with a skewering of 2016 events.

The annual feature Sexiest Woman Alive designation by the magazine is billed as a benchmark of female attractiveness.

Originally, it was a part of the "Women We Love" issue that was released in November. To build interest, the magazine would do a tease, releasing partial images of the woman in the issues preceding the November issue. By 2007, it had become the dominating story of the issue and to create an element of surprise the hints were abandoned.